With good long-term management, the burden of asthma can be reduced.

The Global Asthma Report 2014

Schematic diagram of a pressurised metered dose inhaler.

Figure 1: Schematic diagram of a pressurised metered dose inhaler.

Asthma inhalers are complex devices which require accurate manufacturing. Quality should never be compromised in the search for affordably-priced medicines.

QUALITY OF INHALERS

Asthma inhalers are among the most complex pharmaceutical industry manufactured medical devices in widespread use. To be safe and efficacious, they need to comply with international quality standards. Inhalers of the original brand (innovator) and subsequent products produced by different manufacturers (generics) may meet these standards, but many asthma inhalers in the marketplace do not. Low-resource settings would benefit greatly if the World Health Organization (WHO) Prequalification Programme could include essential asthma medicines and provide its technical support to countries. WHO should promote standardised dosages for combination inhalers and harmonise the quality requirements for inhalers across all the international reference pharmacopoeias.

Inhalers are complex devices

Asthma inhalers, also called ‘pressurised Metered Dose Inhalers’ (pMDI), are among the most complex medical devices manufactured by the pharmaceutical industry. Active ingredients, such as salbutamol or beclometasone, are mixed with a propellant in a canister. When a person presses upwards on the actuator, a standardised dose of the active ingredients is pushed by the metering valve into the mouthpiece Figure 1). The person then inhales the active ingredients into his/her airways, where they should stay and thus be “deposited”. Children, the elderly, and others who have trouble coordinating their movements, should always use pMDI with a spacer or holding chamber attached to optimise delivery of the aerosol into the lungs.

It is important that a high deposition rate is achieved in the lungs and the periphery of the lungs, and that as little medication as possible deposits in the mouth or throat, or gets swallowed into the gastrointestinal tract. This is so the active ingredients can achieve the intended effect on the airways (reliever or preventer). For these reasons, the amount deposited in the lung (pulmonary deposition rate) of a pMDI needs to be measured against internationally agreed standards of efficiency and safety. For adults, the particles of the active ingredient have to be less than 5 micrometres in order to travel efficiently into the patient’s lungs. Only particles between 1 and 3 micrometres will manage to be deposited deep in the lungs. Particles of less than 0.5 micrometres are automatically exhaled and thus have no effect. In children, and particularly in infants and preschoolers, the “breathable” particle size is considerably lower.

Both innovator and generic products have met international standards

A further key requirement for inhalers is to deliver the same quantity of active ingredients (e.g. 100 micrograms of salbutamol) for each of the 200 doses contained in a canister. The fine particle size distribution in the puff, or cloud of the spray, has to conform to strict calibration curves that will allow efficient deposition in the lungs. Manufacturing hundreds of thousands of pMDIs that conform to these strict requirements, batch after batch, year after year, represents a significant technical challenge for pharmaceutical companies. It is no surprise then that only a limited number of manufacturers worldwide have the capacity to produce innovator or generic pMDIs that meet international quality standards. Furthermore, there is a wide variability in the size of the particles in an aerosol generated by pMDIs made by different manufacturers, even for the same medication (e.g. for budesonide). Therefore, manufacturers should be required to specify particle size distribution, so that clinicians can correctly select the best aerosol for each patient.

Nevertheless, innovator and generic single ingredient pMDIs supplied by manufacturers based in the United Kingdom, Spain, India, and Bangladesh have successfully gone through three consecutive qualification processes conducted by the Asthma Drug Facility (ADF) (a project of The Union) between 2008 and 2013, after public and international invitations for Expressions of Interest. These qualifications were based on international quality standards set by the WHO and stringent National Medicine Regulatory Agencies (NMRAs). In addition, generic companies have started to register some of their pMDIs with stringent NMRAs, such as the NMRA in the United Kingdom.

Despite the challenge for generic companies to develop a formulation with the required characteristics, as well as to define the right combination of diameters of the metering valve and the actuator nozzle to dispense the right size of fine particles, several of them have managed to demonstrate the bio-equivalence of their generic products with innovator products. Bio-equivalence means the efficiency and safety of a generic medicine is the same as that of the innovator product and is in compliance with international quality standards. It is one of the fundamental requirements for generics.

In all countries, an NMRA is responsible for ensuring the quality of medicines marketed on their territory. However, according to WHO surveys, 30% of NMRAs, principally those in low-income countries, have limited capacity to perform regulatory functions and 50% have variable capacity to do so, whereas stringent NMRAs are found mainly in wealthier countries. Thus, many NMRAs have major difficulty assessing the innovator and generic pMDIs they want to supply to their populations. This may lead to some treatment failure and/or safety issues.

International measures to support countries

Considering the great global burden of asthma, and that effective medicines for it are available, having quality-assured effective asthma pMDIs is vital. An important step is to have pMDIs added to the WHO Prequalification Programme, which is a centralised quality assessment initiative capable of qualifying products which meet the strict technical criteria discussed above. Since 2001, the centralised quality assessment of medicines for HIV/AIDS, tuberculosis, malaria and reproductive health has achieved greater access for millions of patients to quality-assured medicines for these diseases, even in the least affluent countries. If asthma pMDIs were added to the list, the WHO Prequalification Programme could provide technical assistance to NMRAs in how to assess the inhalers, as well as guidance for manufacturers in how to upgrade their production of asthma inhalers.

The WHO could also contribute to improving the quality of pMDIs circulating globally by promoting the standardisation of the dosages of active ingredients in combined inhalers that are marketed in both high- and low- and middle-income countries. Combined inhalers are made of a bronchodilator (short or long acting β2 agonists) and a corticosteroid. Together they reverse the inflammation in the lungs and have a bronchodilatory (airway-opening) effect. However, there is great variation in the dosages available globally today, especially those including long acting β2 agonists. Such variation is not justified by objective clinical data and creates unnecessary confusion for prescribers, dispensers, patients, and their families.

It would also be greatly beneficial if WHO could promote the harmonisation of quality requirements across current international references, such as the pharmacopoeias (reference books containing directions for the identification of compound medicines) of the United States, the United Kingdom and Europe. These would assist the pharmaceutical industry and NMRAs by having clearer quality standards to work with for the production and assessment of pMDIs. In addition, WHO should modify the requirements for becoming a WHO-prequalification laboratory. These should include the ability to analyse particle size distribution using a cascade impactor. If WHO-prequalified laboratories could provide this service, complemented by a network of qualified university-based laboratories that specialise in analysing aerosols, then NMRAs from low- and middle-income countries would have independent places to test any generic products not already approved by a stringent regulatory authority or a global mechanism such as an Asthma Drug Facility.

Conclusion

The manufacture of asthma inhalers requires accuracy and reliability so that their quality is assured for each dose, and from one inhaler to another. Non-quality-assured asthma inhalers may be ineffective.

Recommendation

The WHO should add essential asthma medicines to their Prequalification Programme, promote the standardisation of the dosages of active ingredients in combined inhalers and the harmonisation of quality requirements for inhalers across international reference documents such as the pharmacopoeias. Governments in all countries should ensure all asthma inhalers procured, distributed, and sold in their countries meet international quality standards.

Christophe Perrin, Luis García-Marcos, Javier Mallol, Karen Bissell

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